Process for producing alpha-phenyl succinimides



United States Patent PROCESS FOR PRODUCING a-PHENYL SUCCINIMIDES Charles A. Miller, Detroit, Mich., assignor to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Application May 2, 1955 Serial No. 505,512

9 Claims. (Cl. 260-3265) This invention relates to a process for producing aphenylsuccinimides. More particularly, the invention relates to a process for producting N-methyl-a-phenylsuccinimide.

N-methyl-a-phenylsuccinimide has recently become a very valuable product for the treatment of petit mal epilepsy. According to United States Patent No. 2,643,- 258 this product can be prepared from phenylsuccinic acid or phenylsuccinic anhydride by reaction with methyamine and heating the resultant product. However, the process sutfers the disadvantage that it requires the use of phenylsuccinic acid or phenylsuccinic anhydride both of which are quite expensive starting materials.

It is an object of the present invention to provide a process for producing N-methyl-u-phenylsuccinimide from readily available cheap starting materials.

In accordance with the invention this object as well as others which will appear hereinafter are realized by reacting phenylmaleic anhydride with methylamine at a temperature between 80 and 110 C. thereby producing N-methyl-wphenylmaleimide and then reducing the aliphatic double bond present in the N-methyl-a-phenylmaleimide.

In carrying out the reaction between the phenylrnaleic anhydride and the methylamine, one equivalent, and preferably a slight excess, of the methylamine is employed. The reaction can be carried out in water, an organic solvent or a mixture of water and a water-miscible organic solvent. Suitable solvents other than water include lower aliphatic alcohols such as methanol, ethanol and isopropanol, cyclic ethers such as dioxane, esters such as ethyl acetate, aqueous mixtures of the aforementioned substances and the like. From the standpoint of cost the preferred solvent is water. The preferred temperature for carrying out the reaction is 95-100 C. The reaction is quite rapid and is usually complete within a half an hour to two hours.

The reduction of the aliphatic double bond in the N- methyl-a-phenylmaleimide is preferably carried out using gaseous hydrogen and a metal hydrogenation catalyst. As hydrogenation catalysts, Raney nickel and the noble metal catalysts such as platinum oxide give particularly good results. The reduction can be carried out at temperatures between and 100 C. The pressure of the gaseous hydrogen is not particularly critical and can be varied anywhere from one atmosphere to a hundred or more. Good results are obtained with hydrogen pressures of about 2 /2 to 6 atmospheres and consequently there is no need to employ greater pressures. As solvents, esters such as ethyl acetate, lower aliphatic alcohols such as methanol, ethanol, isopropanol and mixtures of esters and lower aliphatic alcohols are preferred.

The invention is illustrated by the following example.

Example A mixture consisting of 4 g. of phenylrnaleic anhydride ice and 3.5 ml. of 23% aqueous methylamine is heated on a steam bath for one hour. 10 ml. of cold water is added, the mixture cooled and the desired N-methyl-a-phenylmaleimide collected by filtration; yield 2. g.; M. P. 145-147 C.

100 mg. of platinum oxide hydrogenation. catalyst is added to a solution of 4 g. of N-methyl-a-phenylrnaleimide in 100 ml. of absolute ethanol and 100 ml. of ethyl acetate. The mixture is shaken in a closed vessel with gaseous hydrogen under a pressure of 49 lbs. per sq. inch until the theoretical amount of hydrogen is absorbed. The vessel is vented, the catalyst removed by filtration and the filtrate concentrated to a volume of about 15 ml. The residual liquid is filtered, the filtrate cooled and the desired N-methyl-a-phenylsuccinimide collected; yield 3 g.; M. P. 70-72 C.

If desired, the 100 mg. of platinum oxide catalyst used in the above procedure can be replaced with about 0.5 g. of Raney nickel catalyst.

The phenylrnaleic anhydride used as one of the starting materials in the practice of the invention can be prepared cheaply and easily by the interaction of maleic anhydride, benzene and chlorine in the presence of ultraviolet light.

What I claim is:

1. Process for the production of N-methyl-a-phenylsuccinimide which comprises reacting phenylrnaleic anhydride with methylamine at a temperature between and 110 C. and subjecting the N-methyl-a-phenylmaleimide so produced to the action of a reducing agent for the aliphatic double bond.

2. Process for the production of N-methyl-a-phenyL succinimide which comprises reacting phenylrnaleic anhydride with slightly more than one equivalent of methylamine at a temperature between 80 and 110 C. in an aqueous reaction medium, separating the N-methyl-aphenylrnaleimide so produced and subjecting the N- methyLethenylmaleimide to the action of gaseous hydrogen in the presence of a metal hydrogenation catalyst.

3. Process for the production of N-methyl-a-phenylsuccinimide which comprises reacting phenylrnaleic anhydride with slightly more than one equivalent of methylamine at a temperature between 80 and 110 C. in an aqueous reaction medium, separating the Nmethyl-aphenylmaleimide so produced and subjecting the N- methyl-aphenylmaleimide to the action of gaseous hydrogen at a pressure between 2 /2 and 6 atmospheres and a temperature between 15 and C. in the presence of a noble metal hydrogenation catalyst.

4. Process for the production of N-methyl-a-phenylsuccinimide which comprises reacting phenylrnaleic anhydride with slightly more than one equivalent of methylamine at a temperature between 80 and C. in an aqueous reaction medium, separating the N-methyl-w phenylmaleimide so produced and subjecting the N- methyla-phenylmaleimide to the action of gaseous hydrogen at a pressure between 2 /2 and 6 atmospheres and a temperature between 15 and 100 C. in the presence of Raney nickel hydrogenation catalyst.

5. Process for the production of Nmethyl-wphenylsuccinimide which comprises reacting phenylrnaleic anhydride with methylamine at a temperature between 80 and 110 C., and subjecting the N-methyl-a-phenylmaleimide to the action of gaseous hydrogen in the presence of a metal hydrogenation catalyst.

6. Process according to claim 5 in which the catalyst is selected from the class consisting of Raney nickel and the noble metal catalysts.

7. Process according to claim 5 in which the catalyst. is Raney nickel.

we 1,867 3 8. Process according to claim 5 in which the catalyst is References Cited in the file of this patent Platinum oxide- UNITED STATES PATENTS 9. Process for the production of N-methyl-a-phenylsuccinimide which comprises subjecting N-methyl-a- '2205558 Flatt June 1940 phenylmaleimide'tb' th'e actionof gaseous "hydrogen in'the 5 OTHER REFERENCES presence of a metal hydrogenation catalyst. Sakurai: Chem. Abstracts, vol 31, column 3393 (1937). 

1. PROCESS FOR THE PRODUCTION OF N-METHYL-A-PHENYLSUCCINIMIDE WHICH COMPRISES REACTING PHENYLMALEIC ANHYDRIDE WITH METHYLAMINE AT A TEMPERATURE BETWEEN 80 AND 110*C. AND SUBJECTING THE N-METHYL-A-PHENYLMALEIMIDE SO PRODUCED TO THE ACTION OF A REDUCING AGENT FOR THE ALIPHATIC DOUBLE BOND. 